Strengthening Diagnosis of Pulmonary in Children: The Role of Xpert MTB/RIF Ultra Heather J. Zar, MD, PhD,a Mark P. Nicol, MD, PhDb

Pediatric tuberculosis is a global may be true-positive cases because concern, with children estimated to they were symptomatic, implying an account for 10% to 15% of the overall additional role for Ultra in detecting aDepartment of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital and South African Medical case load, representing almost 1 million culture-negative cases. Research Council Unit on Child and Adolescent Health, cases annually. However, modeling University of Cape Town, Cape Town, South Africa; and estimates indicate that only 30% of However, a high proportion of cases bDivision of Infection and Immunity, School of Biomedical Sciences, The University of Western Australia, Perth, childhood tuberculosis cases are (71%) remained Ultra-positive after Australia diagnosed and notified.1 Diagnosis of 2 months of tuberculosis treatment, pulmonary tuberculosis (PTB) in and there were 3 case patients with Opinions expressed in these commentaries are nontuberculosis lower respiratory tract those of the authors and not necessarily those of the children may be challenging because of American Academy of Pediatrics or its Committees. nonspecific clinical or radiologic signs, infection in whom Ultra results were DOI: https://doi.org/10.1542/peds.2019-2944 paucibacillary disease, and low positive. Ultra may be positive with sensitivity of microbiologic diagnosis.2 a corresponding negative culture if Accepted for publication Sep 10, 2019 However, microbiologic confirmation is there are operational issues in Address correspondence to Heather J. Zar, MD, PhD, needed for accurately defining the transporting, processing or culture of Department of Paediatrics and Child Health, Red ’ samples in the laboratory. No details Cross War Memorial Childrens Hospital, SA MRC Unit burden of disease, effective treatment on Child and Adolescent Health, University of Cape (particularly for drug-resistant were provided on the type of culture Town, 5th Floor, ICH Building, Cape Town 8001, South tuberculosis), and limiting unnecessary testing (solid versus automated liquid) Africa. E-mail: [email protected] use of tuberculosis medication. or decontamination procedures, which PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, may influence the sensitivity of the 1098-4275). 5 Recent advances in specimen collection culture. False-positive Ultra results Copyright © 2019 by the American Academy of with the development of rapid have been reported in adults, Pediatrics molecular diagnostics have improved particularly those previously treated FINANCIAL DISCLOSURE: The authors have indicated 6 the ability to obtain a rapid for tuberculosis, and it is evident from they have no financial relationships relevant to this microbiologic diagnosis. In this edition the current study that Ultra results article to disclose. 3 of Pediatrics, Sun et al report the remained persistently positive through FUNDING: Funded by the Regional Prospective accuracy of Xpert 2 months of treatment in most children. Observational Research in Tuberculosis and tuberculosis and (MTB/RIF) No data were provided on previous cofunded by the South African Medical Research Council and the National Institutes of Health Ultra (Ultra), a next-generation assay tuberculosis treatment in the current 4 (RO1HD058971). Funded by the National Institutes of on the GeneXpert platform, using study, which would also be important Health (NIH). bronchoalveolar lavage (BAL) samples. in interpreting positive Ultra results. An POTENTIAL CONFLICT OF INTEREST: The authors have Ultra had a high sensitivity (91%) additional consideration may be indicated they have no potential conflicts of interest against a microbiologic reference contamination of to disclose. standard of a positive culture result or equipment that may lead to false- COMPANION PAPER: A companion to this article can smear-on-BAL result. Ultra had positive Ultra results.7 Quantitative be found online at www.pediatrics.org/cgi/doi/10. a nonsignificantly higher sensitivity Ultra results were not specifically 1542/peds.2019-0262. than GeneXpert (80% vs 67%). Most reported in the current study but may strikingly, Ultra was positive in the have been useful in interpreting results To cite: Zar HJ and Nicol MP. Strengthening majority (34 of 59; 58%) of children from culture-negative children. Diagnosis of Pulmonary Tuberculosis in clinically diagnosed with PTB in whom However, many children who are Children: The Role of Xpert MTB/RIF Ultra. Pediatrics. 2019;144(5):e20192944 a culture result was negative. These culture-positive have low or trace Ultra

Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 144, number 5, November 2019:e20192944 COMMENTARY results, reflecting the low bacillary The high yield of Ultra on BAL 4. Chakravorty S, Simmons AM, Rowneki load8; the World Health Organization indicates that this should be a first- M, et al. The new Xpert MTB/RIF Ultra: has therefore recommended that low line investigation, together with improving detection of Mycobacterium tuberculosis or trace levels in children be regarded culture testing, in children and resistance to rifampin in an assay suitable for point-of-care as true-positive results.9 Further undergoing bronchoscopy when PTB testing. MBio. 2017;8(4):e00812-17 study of children with positive Ultra is suspected. However, for most but negative culture results is needed children with suspected PTB, BAL 5. Phillips PPJ, Mendel CM, Nunn AJ, et al. to determine if these are cases missed should not and will not be performed; A comparison of liquid and solid by culture testing or are false-positive the current evidence indicates that culture for determining relapse and durable cure in phase III TB trials for results by Ultra. Caution may repeated IS specimens or new regimens. BMC Med. 2017;15(1):207 therefore be needed in interpreting a combination of IS and NPAs provide Ultra-positive results in children. a high yield for testing with Ultra. 6. Dorman SE, Schumacher SG, Alland D, et al; Study Team. Xpert MTB/RIF Ultra The high sensitivity of Ultra for However, there remains a large group of children who are clinically for detection of Mycobacterium Mycobacterium tuberculosis and tuberculosis and rifampicin resistance: diagnosed with negative culture rifampicin resistance on BAL is an a prospective multicentre diagnostic important advance for diagnosis in results, highlighting the pressing need accuracy study. Lancet Infect Dis. 2018; children. Unfortunately, BAL is rarely for a better diagnostic test to 18(1):76–84 available in high-burden tuberculosis distinguish those children who truly have tuberculosis among the 7. Kaul K, Luke S, McGurn C, et al. areas because it requires Amplification of residual DNA unconfirmed tuberculosis cases. considerable resources and expertise, sequences in sterile bronchoscopes which make it unsuitable for a point- Because most cases of childhood leading to false-positive PCR results. of-care diagnostic specimen. tuberculosis occur in low- and J Clin Microbiol. 1996;34(8):1949–1951 middle-income countries, a better, Alternative respiratory specimens 8. Zar HJ, Workman LJ, Prins M, et al. rapid, accurate, point-of-care that are more easily obtainable Tuberculosis diagnosis in children diagnostic for use in these settings is include nasopharyngeal aspirate using Xpert Ultra on different (NPAs), induced (IS), or a priority. respiratory specimens [published gastric lavage. Importantly, in online ahead of print August 5, 2019]. children, repeated specimens Am J Respir Crit Care Med. doi:10.1164/ ABBREVIATIONS significantly improve diagnostic rccm.201904-0772OC sensitivity.8,10,11 Ultra on IS was BAL: bronchoalveolar lavage 9. World Health Organization. Automated recently reported to have high IS: induced sputum real-time nucleic acid amplification sensitivity, with an incremental yield NPA: nasopharyngeal aspirate technology for rapid and simultaneous for repeated specimens observed in PTB: pulmonary tuberculosis detection of tuberculosis and low- and middle-income countries.8 A rifampicin resistance: Xpert MTB/RIF single NPA Ultra had a sensitivity of Assay for the Diagnosis of Pulmonary and Extrapulmonary TB in Adults and up to 46%, Ultra tests on 2 sequential REFERENCES Children. Policy update. 2013. Available NPAs increased this to 54%, whereas 1. Dodd PJ, Gardiner E, Coghlan R, Seddon at: https://apps.who.int/iris/bitstream/ a single Ultra on IS had a sensitivity of JA. Burden of childhood tuberculosis in handle/10665/112472/9789241506335_ 74%, and a single IS and NPA further 22 high-burden countries: eng.pdf?sequence=1&isAllowed=y. increased this to 80%. The highest a mathematical modelling study. Lancet Accessed September 6, 2019 sensitivity (87%) was obtained by Glob Health – . 2014;2(8):e453 e459 10. Sabi I, Rachow A, Mapamba D, et al. testing 2 NPAs and a single IS 2. Connell TG, Zar HJ, Nicol MP. Advances Xpert MTB/RIF Ultra assay for the fi compared with culture-con rmed in the diagnosis of pulmonary diagnosis of pulmonary tuberculosis in 9 cases. Importantly, in the current tuberculosis in HIV-infected and HIV- children: a multicentre comparative study, no comparison in yield by uninfected children. J Infect Dis. 2011; accuracy study. J Infect. 2018;77(4): using Ultra on repeated IS samples 204(suppl 4):S1151–S1158 321–327 compared with BAL was performed, 3. Sun L, Qi X, Liu F, et al. Added-value of 11. Nicol MP, Workman L, Prins M, et al. so it is unknown how many children Xpert MTB/RIF Ultra in accurate Accuracy of Xpert MTB/RIF Ultra for the may have been diagnosed on IS, or diagnosis of pulmonary tuberculosis in diagnosis of pulmonary tuberculosis in other less invasive specimens, sparing children. Pediatrics. 2019;144(5): children. Pediatr Infect Dis J. 2018; them a bronchoscopy and BAL. e20190262 37(10):e261–e263

Downloaded from www.aappublications.org/news by guest on September 27, 2021 2 ZAR and Nicol Strengthening Diagnosis of Pulmonary Tuberculosis in Children: The Role of Xpert MTB/RIF Ultra Heather J. Zar and Mark P. Nicol Pediatrics originally published online October 25, 2019;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2019/10/23/peds.2 019-2944 References This article cites 10 articles, 2 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2019/10/23/peds.2 019-2944#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Infectious Disease http://www.aappublications.org/cgi/collection/infectious_diseases_su b Pulmonology http://www.aappublications.org/cgi/collection/pulmonology_sub Respiratory Tract http://www.aappublications.org/cgi/collection/respiratory_tract_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 27, 2021 Strengthening Diagnosis of Pulmonary Tuberculosis in Children: The Role of Xpert MTB/RIF Ultra Heather J. Zar and Mark P. Nicol Pediatrics originally published online October 25, 2019;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/early/2019/10/23/peds.2019-2944

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